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The expression of sex steroid receptors and sex steroid-synthesizing/metabolizing enzymes in metastasized lymph nodes of prostate cancer

Nakamura Y, Ise K, McNamara KM, Azmahani A, Sato S, Fujishima F, et al.

Hum Pathol, 2019 02;84:124-132.
PMID: 30290162 DOI: 10.1016/j.humpath.2018.09.011

The expression statuses of sex steroid receptors and sex steroid-synthesizing/metabolizing enzymes have been reported in primary prostate cancer lesions, but that in metastatic lymph nodes has remained unknown. Therefore, in this study, we immunolocalized these proteins in primary tumors and paired metastatic lymph nodes of prostate cancer and correlated the findings with clinicopathological factors of individual patients. The expression statuses of AR and ER β was significantly increased in metastatic lymph nodes compared with primary lesions, whereas that of 17βHSD1, 17βHSD2, 17βHSD5, and STS immunoreactivity was decreased in metastatic lymph nodes. In metastatic lymph nodes, the status of 5α2 was significantly correlated with that of AR. In addition, 17βHSD5-, 5α1-, STS-, and EST-positive cases were significantly associated with Gleason score (GS) status (GS > 8 versus GS < 7) in metastatic lymph nodes. Results of our present study did demonstrate that in situ androgen and estrogen metabolism and action play roles in pathophysiology of prostate cancer in metastatic lymph nodes, but these steroidogenic effects could be different from those in primary lesions.
Expression of AR, 5αR1 and 5αR2 in bladder urothelial carcinoma and relationship to clinicopathological factors

Hata S, Ise K, Azmahani A, Konosu-Fukaya S, McNamara KM, Fujishima F, et al.

Life Sci, 2017 Dec 01;190:15-20.
PMID: 28947209 DOI: 10.1016/j.lfs.2017.09.029

AIMS: Bladder urothelial carcinoma is increasing in incidence with age and its prognosis could become worse when accompanied with metastasis. Effective treatment of these advanced patients is required and it becomes important to understand its underlying biology of this neoplasm, especially with regard to its biological pathways. A potential proposed pathway is androgen receptor (AR)-mediated intracellular signaling but the details have remained relatively unexplored.
MAIN METHODS: The expression of AR, 5α-reductase type1 (5αR1) and 5α-reductase type2 (5αR2) were examined in the bladder cancer cell line T24 and surgical pathology specimens. We also evaluated the status of androgen related cell proliferation and migration using the potent, non-aromatizable androgen agonist 5α-dihydrotestosterone (DHT).
KEY FINDINGS: DHT treatment significantly increased AR mRNA expression level, but not those of 5αR1 and 5αR2 in T24 cells. DHT also suppressed cellular migration with weaker and opposite effects on cell proliferation. A significant inverse correlation was detected between pT stage and AR, 5αR1 and 5αR2 immunoreactivity.
SIGNIFICANCE: Inverse correlations detected between tumor grade and AR/androgen metabolizing enzyme also suggested that the loss of AR and androgen-producing enzymes could be associated with tumor progression. Effects of DHT on cells also suggest that androgens may regulate cellular behavior.
Steroidogenic enzymes, their related transcription factors and nuclear receptors in human sebaceous glands under normal and pathological conditions

Azmahani A, Nakamura Y, Felizola SJ, Ozawa Y, Ise K, Inoue T, et al.

J Steroid Biochem Mol Biol, 2014 Oct;144 Pt B:268-79.
PMID: 25090634 DOI: 10.1016/j.jsbmb.2014.07.010

The sebaceous gland is a major site of steroid synthesis in human skin, but details of the status of steroidogenic enzymes and their regulation in human sebaceous glands under normal and pathological conditions have rarely been reported. Therefore, in this study, we examined the status of steroidogenic enzymes, sex steroid receptors and transcription factors in human sebaceous glands under normal and pathological conditions to explore their possible roles in in situ steroid production in human skin. Immunohistochemical analysis was performed in a total of 59 human skin specimens, including 22 normal human sebaceous glands, 12 with sebaceous nevus, 12 with sebaceous gland hyperplasia, 3 with sebaceoma and 10 with sebaceous carcinoma. Immortalised human SZ95 sebocytes were treated with forskolin or vehicle for 3h, 6h, 12h or 24h, and the mRNA levels of steroidogenic enzymes were evaluated at each time point using quantitative RT-PCR (qPCR). The results of immunohistochemistry demonstrated the immunoreactivity of 3β-HSD1, CYP11A1, StAR, 17β-HSD5, CYP17A1, 5α-red1, PRB, AR and NGFI-B in normal human sebaceous gland, with lower levels of expression in pathological sebaceous glands. The results of the in vitro study also indicated that the expression levels of 3β-HSD1, CYP11A1, StAR, 5α-red1 and NGFI-B were elevated by forskolin. 3β-HSD1 and other steroidogenic enzymes were expressed in sebaceous glands resulting in in situ androgen and progesterone synthesis and their functions.
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Azmahani A, Nakamura Y, Felizola SJ, Ozawa Y, Ise K, Inoue T, et al.

J Steroid Biochem Mol Biol, 2016 Jan;155(Pt A):178-80.
PMID: 26455405 DOI: 10.1016/j.jsbmb.2015.09.028